Prolonged hypergastrinemia causes proliferation of gastric enterochromaffin-like cells (ECL cells) which can progress to the development of carcinoid tumors, some of which are malignant. With the increased chronic treatment of such common conditions as gastroesophageal reflux disease (GERD), with H-+-K-+ ATPase inhibitors (omeprazole, etc.), which are potent acid suppressants and can cause hypergastrinemia in >80% of patients, there is increased concern over the longterm effects on gastric ECL cells in humans. Currently, little is known about the effects in humans of hypergastrinemia alone because in most diseases it occurs also with gastritis and gastric atropy which can effect ECL changes. Patients with Zollinger-Ellison syndrome (ZES) have life-long hypergastrinemia because most are not cured and therefore are excellent models to study the gastric effects of hypergastrinemia alone. To address the effects of chronic hypergastrinemia in man on gastric ECL cells as well as determine the frequency of carcinoid tumors with hypergastrinemia, the best methods to detect them and the identification of contributing factors, a series of long-term prospective studies have been started in collaboration with Prof. C. Bordi, Dept. of Pathology, Univ. of Pharma, Italy and Prof. G. Delle Fave, La Sapienza, Rome, Italy. In a recent prospective study involving 106 consecutive patients with sporadic ZES we found 99% had ECL hyperplasia and abnormal alpha-HCG staining in gastric biopsies with 50% having advanced ECL changes. No patient had carcinoid. The extent of ECL hyperplasia correlated closely with the magnitude of hypergastrinemia, but was not affected by gender, or vagotomy, both of which had an effect in animal studies. These results show prolonged hypergastrinemia in man alone can cause advanced ECL changes, no threshold exists as proposed by others and the risk of carcinoids in man with hypergastrinemia only is low. Furthermore, this study showed alpha-HCG intensity is an independent predictor of dysplasia and should be routinely used in gastric biopsies of hypergastrinemic studies. Similar studies are now underway in patients with ZES and MEN1 who have an increased risk of developing gastric carcinoids.